DESCRIPTION: (Applicant's Abstract) Marijuana is one of the most widely used drugs of abuse in the world, and it is the goal of this proposal to understand the neurobiological basis for its effects on synaptic function. Marijuana and its constituent cannabinoids have been shown to have analgesic, antiemetic and antiglaucoma properties, but the psychoactive side effects of these drugs - most notably, cognition and memory impairments - make them undesirable as therapeutic agents. These detrimental effects are likely to be mediated, at least in part, by alteration of the normal synaptic functioning of the hippocampus, a brain region that plays a central role in certain forms of learning and memory. This proposal describes a series of experiments to determine the cellular and molecular basis for the effects of cannabinoids on hippocampal synaptic function. Using electrophysiological techniques, the acute and chronic effects of cannabinoids on four aspects of basic synaptic function, and on four forms of synaptic plasticity - some of which are believed to form the cellular basis for learning and memory - will be determined. Using a pharmacological approach, the role of calcium and potassium channel modulation in cannabinoid-mediated effects will be determined. Using a combination of pharmacological and molecular biological approaches, the roles of different classes of G-proteins in cannabinoid-mediated effects will be determined. Understanding the cellular and molecular basis for the effects of cannabinoids on cognition and memory is a necessary first step in the rational design of selective therapeutic agents that can replicate the beneficial properties of cannabinoids without their negative psychoactive side effects. The proposed studies enhance memory or reverse memory loss. Finally, understanding the neurobiological basis for the effects of cannabinoids may aid in drug abuse prevention and treatment.